Neuroscience and Biobehavioral Reviews 35 (2011) 2084–2093

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Neuroscience and Biobehavioral Reviews

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Review

Interplay of excitation and inhibition elicited by tonal stimulation in pyramidal

neurons of primary auditory cortex
Hisayuki Ojima ∗
Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8749, Japan

a r t i c l e i n f o a b s t r a c t

Article history: Tonal responses of neurons in the primary auditory cortex are a function of frequency, intensity and ear of
Received in revised form 19 October 2010 stimulation. These responses occasionally display suppression. This review discusses how excitatory and
inhibitory synaptic inputs interact to form suppressive responses and how changes in stimulus attributes
Keywords: affect the magnitude and timing of those responses.
Primary auditory cortex Stimulation at the characteristic frequency evokes a stereotyped sequence of depolarization (excita-
Suppression
tory) and then hyperpolarization (inhibitory), as predicted from the canonical circuitry. Some neurons
Excitatory postsynaptic potential
stimulated at higher sound intensities display a prominent increase in the magnitude of hyperpolar-
Inhibitory postsynaptic potential
Non-monotonic rate-level function
ization or a decrease in its latency, both enabling counteraction with the preceding excitation. These
Binaural interaction interactions, in part, underlie the non-monotonic suppression. Furthermore, monaural non-dominant
Spontaneous discharge ear stimulation elicits such a powerful hyperpolarization as to cancel out the depolarization elicited at
Laminar difference dominant ear stimulation, suggesting a linear mechanism for the binaural suppression. Alternatively, it
elicits a depolarization almost equal in magnitude and time course to that elicited at binaural stimulation,
suggesting a nonlinear interaction responsible for the suppression. Laminar differences are also noted
for these inhibitory interactions.
© 2010 Elsevier Ltd. All rights reserved.

Contents

1. Cortical circuitry and inhibitory neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2084

2. Involvement of GABAergic interneurons in stimulus specific responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2085
3. EPSP and IPSP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2085
4. Response variability revealed at near-threshold intensity of the CF tones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2086
5. Spontaneous responses as singular or clustered APs and inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2087
6. Forms of suppression observed in AI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2088
7. Suppression in the non-monotonic rate-level function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2088
7.1. Membrane potential changes elicited in non-monotonic responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2088
7.2. Direct measurement of synaptic currents by in vivo whole-cell patch clamp . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2089
8. Synaptic activation in the binaural interaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2090
9. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2091
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2091

1. Cortical circuitry and inhibitory neurons (Kawaguchi and Kondo, 2002; Markram et al., 2004; Miles, 2000).
Aside from spiny stellate cells, they are biochemically defined to
The neocortical network is comprised of two classes of neu- contain GABA as a neurotransmitter and have been referred to
rons, pyramidal neurons (PNs) and interneurons. Interneurons as inhibitory interneurons, since GABA distances the membrane
are known to consist of heterogeneous cell types with distinct potential of postsynaptic neurons from the threshold for spike
local axon collateralizations and characteristic dendritic arbors generation in adults. More recent studies have revealed the colo-
calization of various neuropeptides with morphologically distinct
GABAergic interneurons. The GABAergic interneurons occur rela-
∗ Tel.: +81 3 5803 5445; fax: +81 3 5803 0186. tively infrequently within the neocortex (approximately 20–25%
E-mail address: yojima.cnb@tmd.ac.jp of the neuronal population; Hendry et al., 1987; Prieto et al., 1994)

0149-7634/$ – see front matter © 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.neubiorev.2010.11.009
 H. Ojima / Neuroscience and Biobehavioral Reviews 35 (2011) 2084–2093 2085

Fig. 1. Schemes of simplified connections of neurons in primary auditory (AI) cortex and the ascending pathway to the AI cortex. (A) As in other primary cortical fields,
neurons in thalamocortical (TC)-recipient zone of the AI cortex receive thalamic afferents from a specific nucleus, the ventral nucleus of the medial geniculate complex (MGC)
as sensory afferents, and association and callosal afferents as extrinsic input (extrinsic). Participants in AI intrinsic connection include recurrent collaterals (recurrent) of
nearby pyramidal neurons (PNs), horizontal collaterals of supragranular PNs (pt) located at remote loci within the AI (intrinsic; Ojima et al., 1991, 1992), and collaterals of
local interneurons. Note that a minicolumn has a horizontal width of 50–75 ␮m (Winer, 1984) and the horizontal extent of a TC afferent is 250 ␮m in diameter (Hashikawa
et al., 1995; Cetas et al., 1999). Pyramidal neurons, triangles; GABAergic interneurons, ovals; TC neurons, circles; and extrinsic neuron, square. (B) There are three major
commissural projections in the auditory ascending pathway; at the level of the cochlear nucleus, the inferior colliculus, and cortex (corpus callosum).

and the range of their proportions in different layers is relatively
small (15–30% Hendry et al., 1987), except for layer 1 in which
more than 90% of the neurons are GABAergic. Despite their rela-
tively infrequent occurrence, the GABAergic interneurons play a
very important role in the regulation of neuronal excitability, con-
struction of receptive field properties, temporal precision of spike
timing, and signal synchronization leading to the generation of cor-
tical rhythms (Bacci and Huguenard, 2006; Creutzfeldt et al., 1974;
Ferstet and Koch, 1987; Fricker and Miles, 2001; Oswald et al., 2009;
Sadagopan and Wang, 2010; but see Priebe and Ferster, 2008).
Excitability of neurons in a small cortical domain or column is
determined by afferents of multiple sources such as thalamocor-
tical (TC) neurons, cortical interneurons, neighboring PNs, distant
but within-field PNs, and association and callosal neurons (Fig. 1).
Response properties of sensory cortical neurons in the primary
recipient zone of TC afferents are largely determined by a network
involving feedforward activation of pyramidal/spiny stellate neu-
rons and GABAergic interneurons, known as canonical circuitry.
This model was originally proposed for the visual cortex, includ-
ing both supragranular and infragranular microcircuits (Douglas
and Martin, 1991, 2004), but is likely to be also applicable at least
to supragranular layer in the auditory cortex, (Cruikshank et al.,
2002; Shu et al., 2003; Rose and Metherate, 2005; Richardson et al.,
2009).
2. Involvement of GABAergic interneurons in stimulus
specific responses
Unlike the primary visual field, typical spiny stellate neurons are
very rare in layer 4 of the primary auditory (AI) field (Fitzpatrick and
Henson, 1994; McMullen and de Venecia, 1993; Meyer et al., 1989;
Smith and Populin, 2001; Winer, 1984), and PNs in layer 4 and lower
layer 3 are regarded as the major recipients of TC afferents in the
auditory system (Hashikawa et al., 1995; Huang and Winer, 2000;
McMullen and de Venecia, 1993; Smith and Populin, 2001).
In the auditory canonical circuitry, TC afferents are derived
from the ventral nucleus of the medial geniculate complex (vMGC).
Synaptic transmission to the cortical recipient neurons is highly
reliable (Rose and Metherate, 2005), and this may be due to the
preferential positioning of TC synapses at locations near the soma
(Richardson et al., 2009). Response properties of AI neurons are
generated by simple inheritance of thalamic activities, linear con-
struction from simple to complex receptive fields, or nonlinear
assembly of distinct activities (Creutzfeldt et al., 1980; Miller et al.,
2001). However, it is also very likely that they depend on cortical
circuitry involving diverse types of interneurons (McMullen and
Glaser, 1982; Prieto et al., 1994), just as in the model proposed for
the primary visual field in which interactions of inhibition with
excitation serve to refine various stimulus selectivities (Ferstet and
Koch, 1987; Shapley et al., 2003). In this review, by relating spike
rate changes to behaviors of membrane potentials, I propose pos-
sible wiring schemes which may account for the responses derived
from interactions of excitation and inhibition evoked by tonal stim-
ulation, usually at the neuron’s characteristic frequency (CF).
3. EPSP and IPSP
A stimulus-evoked hyperpolarized deflection of membrane
potential (inhibitory postsynaptic potential, IPSP) following a depo-
larized membrane potential (excitatory postsynaptic potential,
EPSP) at the onset of acoustic stimulation was revealed by elec-
trophysiological recordings of membrane potentials from single AI
neurons with conventional sharp glass-microelectrodes (Ojima and
Murakami, 2002; De Ribaupierre et al., 1972; Volkov and Galazjuk,
1991; Volkov and Galazyuk, 1992). A similar sequence of EPSP
and IPSP was also induced by electrical stimulation of the MGC
(Mitani et al., 1985). GABA agonist/antagonist application directly
into AI dramatically changed the frequency response field and
frequency-intensity function both in vivo (Chen and Jen, 2000; Kaur
et al., 2004; Wang et al., 2000, 2002) and in vitro (Broicher et al.,
2010). Beyond the stimulus-driven induction of inhibitory activ-
ity or its anti-epileptic effect, findings have accumulated as to how
inhibitory inputs serve to shape acoustic receptive fields (Liu et al.,
2007; Ojima and Murakami, 2002; Tan et al., 2004, 2007; Tan and
2086 H. Ojima / Neuroscience and Biobehavioral Reviews 35 (2011) 2084–2093
Fig. 2. Canonical circuitry and possible response sequences of excitation and inhi-
bition predicted from the circuitry. (A) Scheme explaining the canonical circuitry in
which TC neurons in the ventral nucleus of the MGC sends feedfoward projections
to PNs (open triangle) as well as interneurons (filled circle), which in turn send
inhibitory projections to the PNs. (B) Different sequences of excitation and inhi-
bition (types I–IV) are predicted in the pyramidal neurons depending on whether
activation of the pyramidal neurons and interneurons of the canonical circuitry is
suprathreshold or subthreshold (see A for possible combinations of suprathresh-
old and subthreshold responses). (C) Stimulation with the neuron’s characteristic
frequency at a fixed intensity slightly above threshold for spike generation elic-
its fluctuated responses that are suprathreshold in some trials and subthreshold
in other trials. This fluctuation is represented by differently colored postsynaptic
membrane potentials elicited. Each neuron elicits only two types of the response
sequences shown schematically in B. Combination A, type I or type IV. Combination
B, type I or type III. Combination C, type II or type IV. Combination of type II and type
III is never observed. Each trace is a single trial. Vertical think bars indicate 5 mV.
Horizontal thick bars indicate the stimulus period of 50 ms.
Wehr, 2009; Wehr and Zador, 2003; Wu et al., 2006, 2008), how
they define direction selectivity to frequency-sweep sounds (Ye
et al., 2010; Zhang et al., 2003), how they regulate temporal dis-
charge patterns (Huetz et al., 2009; Wehr and Zador, 2005), and
how they are involved in the response properties related to or
assumed to be related to the spatial localization of a sound source
(Chadderton et al., 2009; Ojima and Murakami, 2002).
EPSP and IPSP recorded from PNs at the stimulus onset, espe-
cially in the TC recipient zone (layer 4 and lower layer 3), are elicited
chiefly by activation of excitatory input from the thalamus and
inhibitory input from the cortex. These oppositely deflected post-
synaptic potentials (PSPs) show variability in their magnitude and
timing according to the varying stimulus attributes. Canonical cir-
cuitry (Fig. 2A) has been proposed as the basic network underlying
these interactions (Douglas and Martin, 1991, 2004; Liu et al., 2007;
Oswald et al., 2006; Zhou et al., 2010). Its simplified connectivity,
however, does not explain the full range of response diversities of
AI neurons (Liu et al., 2007). Especially, since the distribution of
TC afferents is heterogeneous across cortical supragranular layers
(Hashikawa et al., 1995; Huang and Winer, 2000; McMullen and
de Venecia, 1993), response diversities are likely to vary signifi-
cantly between neurons in different layers (Atencio and Schreiner,
2010a,b; Ojima and Murakami, 2002). Thus, it is predicted that
the interactions of excitatory and inhibitory synaptic inputs to PNs
result in diverse patterns in different layers.
4. Response variability revealed at near-threshold intensity
of the CF tones
Excitability of AI neurons can be demonstrated in the tuning
curve constructed on a frequency and intensity matrix from which
an optimal stimulus frequency is defined as the CF at the mini-
mum threshold intensity (Schreiner, 1992). It was observed that,
at or slightly above the threshold, spike generation was not fully
secured but fluctuated on a trial-by-trial basis. Namely, in repeated
presentation of the same CF tone, some trials succeeded in evoking
spikes in AI PNs, but other trials failed. If this fluctuation in fir-
ing is examined in terms of membrane potential changes, we will
see occurrence of an EPSP either with or without action potentials
(EPSP + APs or subthreshold EPSP) at the onset of acoustic stim-
ulation and, possibly, after a short delay, an IPSP. The canonical
circuitry suggests that the critical determinant of IPSP generation in
PNs is whether or not the activation of cortical GABAergic interneu-
rons by TC afferents is suprathreshold.
The cortical network may be more complicated than that repre-
sented by the canonical circuitry. Depending on whether responses
of the cortical PN and interneuron in the canonical circuitry
cross the threshold or remain below, four different patterns of
excitation–inhibition sequence can be expected for individual PNs.
Thus, suprathreshold EPSP (supraEPSP) elicited both in the PN and
interneuron will yield a typical membrane potential sequence start-
ing with an EPSP + AP followed by an IPSP (type I sequence) in this
PN. Similarly, supraEPSP in the PN and subthreshold EPSP (subEPSP)
in the interneuron will yield an EPSP + AP only (type II sequence) in
the PN. Moreover, subEPSP in the PN and supraEPSP in the interneu-
ron will yield a subEPSP followed by an IPSP (type III sequence), and
subEPSP elicited both in the PN and interneuron will yield a subEPSP
alone (type IV sequence) (see Fig. 2B).
Each of these 4 response types would be potentially available
for every neuron. However, for responses to many repeats of a
stimulus tone with the same CF at the intensity slightly above
threshold, only two types of sequences occurred in each neuron
(Fig. 2C, unpublished observation). Many AI neurons (16/40) dis-
played either a type IV or I sequence in the fluctuated response
(combination A). The majority of neurons (20/40) showed either
a type III or I sequence (combination B). Nearly 10% of PNs (4/40)
exhibited either a type II or IV sequence (combination C). We never
observed PNs that showed other possible combinations such as
type II and type III sequence as the fluctuated responses. Consider-
ing that stronger neuronal activation is needed for the generation
of an supraEPSP (in type II sequence) than of an subEPSP (in type
III sequence), this combination indeed may not be possible unless
we assume GABAergic interneurons with the non-monotonic rate-
level function to explain the absence of an IPSP following the
supraEPSP of type II sequence. The non-random arrangement of
these patterns of synaptic sequences is presumably the reflection
of some anatomical constraints in association with synaptic inputs
to individual PNs, interneurons or both.
Each layer has a distinct local network. Indeed, the diverse pat-
terns of synaptic sequences in individual PNs can be ascribed in part
to their different laminar localizations. By iontophoretically inject-
ing a dye filled in the glass-microelectrode used for intracellular
recording, neurons can be labeled for their laminar locations. This
showed that almost all PNs recorded in layer 2 showed a type II or IV
sequence (Ojima and Murakami, 2002). Their onset EPSP (onEPSP),
irrespective of AP generation or failure, is not followed by IPSP. This
implies that the canonical-like circuitry is not the dominant type
 H. Ojima / Neuroscience and Biobehavioral Reviews 35 (2011) 2084–2093 2087

Fig. 3. Relationship between the number of spikes and the IPSP amplitude following them. Membrane potential changes in response to repeated presentation (stimulus
interval, 1.1 s) of a single stimulus tone with the neuron’s characteristic frequency at 10 dB above the minimal threshold intensity (left) and those occurring spontaneously
(right). Uppermost traces show superimposition of all trials, with prominently larger hyperpolarizations pointed by small arrows. Note mixture of traces with small or large
amplitudes of IPSPs in both stimulated and spontaneous cases. The IPSPs with larger amplitudes are almost always preceded by a burst of action potentials, i.e., triple spikes
(lower left, red traces) for evoked firing, or double or more-than-double spikes for spontaneous firing (lower right, red traces). Horizontal lines in superimposed and individual
traces indicate resting membrane potential levels.

of connection in layer 2 and, probably, upper layer 3. Such differ-
ences in local synaptic interactions may also be related to laminar
diversity of dynamic sound processing of PNs in cat AI (Atencio and
Schreiner, 2010a,b; Huggenberger et al., 2009; Sakata and Harris,
2009).
5. Spontaneous responses as singular or clustered APs and
inhibition
In addition to stimulus-driven APs, chiefly via activation of
TC input, APs also occur spontaneously in a singular or bursting
mode (Eggermont, 1992; Valentine and Eggermont, 2001). It was
observed in some neurons that no IPSP followed spontaneous APs
when they were singular (De Ribaupierre et al., 1972; Tan et al.,
2004), but that an IPSP frequently followed spontaneous APs when
they were clustered (Fig. 3, unpublished observation). Single PNs
in cat AI have a rich plexus of local collaterals with an extent of
approximately 500 ␮m in diameter around the cell of origin (Ojima
et al., 1991, 1992). These collaterals are most likely to make synaptic
contacts with nearby neurons including GABAergic interneurons,
which in turn make inhibitory synaptic contacts with the PNs from
which the axon collaterals are derived. Data from the auditory cor-
tex are limited (Atzori et al., 2001; Barbour and Callaway, 2008;
Oswald and Reyes, 2008; Oswald et al., 2009), but, in many sen-
sory systems, recurrent network is formed both between different
PNs and between PNs and interneurons (Holmgren et al., 2003;
Sanchez-Vives and McCormick, 2000; Staiger et al., 2002, 2009;
Thomson and Lamy, 2007). This raises the possibility that APs
evoked spontaneously in a presynaptic PN, when they are singular,
are not sufficient to bring the membrane potential of postsynap-
2088 H. Ojima / Neuroscience and Biobehavioral Reviews 35 (2011) 2084–2093

Fig. 4. Two representative response patterns of suppression found in the non-monotonic amplitude-versus-level function. Stimulus periods are shown by thick lines on time
axis. (A) As sound intensity increases from 35 to 70 dB SPL, amplitude of the onEPSP decreases in association with its decreasing duration, probably caused by increasingly
earlier onset of IPSP as tone intensity increases (short arrows). Individual traces represent the average of 10 repeated responses. Characteristic frequency of this pyramidal
neuron is 14.3 kHz. (B) As sound intensity increases from 10 to 80 dB SPL, amplitude of the onEPSP, together with decreasing firing rate (shown in parentheses), decreases in
association with the increasing amplitude of the IPSP following it. Characteristic frequency of this pyramidal neuron is 20.1 kHz. From Ojima and Murakami (2002).

tic interneurons above threshold. However, when spontaneous APs
occur in the PN more than once during a narrow time window (i.e., a
burst), probably owing to the temporal summation of EPSP elicited
by each of the APs of a burst, these APs easily bring membrane
potentials of the postsynaptic interneurons above threshold, thus
entailing AP generation in these interneurons. The APs generated in
the GABAergic interneurons in turn elicit IPSPs in the presynaptic
PN in a reciprocal manner.
Reduced spike count immediately after burst-like click trains
has been reported in vivo (Eggermont, 1992), although it is not
known how the changes in firing mode of AI neurons are related
to sound processing. Intracortical electrical stimulation at high
rates increased the occurrence of bursting activities and led to
changes in cross-correlation between neuronal pairs (Valentine
and Eggermont, 2003). It also accompanied a shift in the CFs of
neurons at the stimulation site. Thus, elevated activity at a certain
cortical site may alter the synchronization pattern of cortical neu-
rons, presumably necessary for the changed perception of acoustic
attributes. It is conceivable that the occurrence of strong inhibition
following burst firing may be involved in changes in the neuronal
synchronization.
6. Forms of suppression observed in AI
Suppression, reflected by reduced spike count, is known to
shape various forms of response properties of auditory cortical
neurons. Representative suppressions in the AI cortex include: (1)
lateral side-band suppression, i.e., reduction in firing rate at the
neuron’s CF tone by prior or simultaneous presentation of an addi-
tional tone at different frequencies (Brosch and Schreiner, 1997;
Calford and Semple, 1995; Sutter and Schreiner, 1995; Sutter et al.,
1999); (2) suppression in non-monotonic rate versus level func-
tion, i.e., reduction in firing rate at higher sound intensities (Brugge
et al., 1969; Heil et al., 1994; Pfingst and O’Connor, 1981; Phillips
and Cynader, 1985; Phillips and Irvine, 1981; Suga, 1977; Sutter
and Schreiner, 1995); and (3) suppression in binaural interaction,
i.e., reduction in firing rate at stimulation of both ears relative to
stimulation of one ear alone (Benson and Teas, 1976; Brugge et al.,
1969; Brugge and Merzenich, 1973; Calford and Semple, 1995;
Hall and Goldstein, 1968; Imig and Adrián, 1977; Imig and Brugge,
1978; Imig and Reale, 1981; Kitzes et al., 1980; Middlebrooks et al.,
1980; Phillips and Cynader, 1985; Phillips et al., 1985; Phillips and
Irvine, 1983; Semple and Kitzes, 1985). Suppression of spontaneous
and stimulus-driven discharges is also known to occur during self-
vocalization of monkeys (Eliades and Wang, 2003; Müller-Preuss
and Ploog, 1981).
How EPSP and IPSP interact to suppress the responses
of AI neurons was systematically examined by intracellularly
recording membrane potentials using conventional sharp glass-
microelectrodes (Ojima and Murakami, 2002). The results revealed
counteractions of EPSP and IPSP in a stimulus-dependent manner
by virtue of the disproportionate growth of IPSP, advanced onset of
IPSP, and suppressive influences of non-dominant ear stimulation
on dominant ear stimulation.
7. Suppression in the non-monotonic rate-level function
7.1. Membrane potential changes elicited in non-monotonic
responses
At least two types of interactions of EPSP and IPSP have been
elucidated for neurons showing the non-monotonic rate-level
function of spike discharge. The first interaction underlying the
reduced spike discharge (Fig. 4A) is that the onset latency of the
IPSP becomes shortened to a much greater extent than that of the
preceding onEPSP as sound intensity increases. Because of this ear-
lier onset of IPSP, the peak/falling phase of the preceding EPSP is
chipped off, leading eventually to a shorter duration and decreased
amplitude. Thus, at higher sound intensities, EPSP and IPSP come
to counteract in a summative manner (Eccles, 1968), since they
become temporally coincident. The shortened duration of onEPSP
also leads to a reduced jitter in the onset timing of evoked APs or a
more consistent delay of the AP onset across trials. This is due to a
narrower time window for the onEPSP to become suprathreshold.
In another type (Fig. 4B), as sound intensity increases, the IPSP peak
amplitude increases greatly to such a degree that the preceding
onEPSP amplitude becomes substantially reduced. Here, delay time
of the IPSP appears to contribute little to the reduced amplitude of
the preceding onEPSP. This results in a decreased spike count.
These types of interaction of EPSP and IPSP underlying the non-
monotonic firing pattern are typically observed for PNs located in
the TC recipient zone of the AI cortex. Neurons in layer 2, however,
show different membrane potential behaviors. EPSP is elicited in
layer 2 PNs but is not eventually followed by IPSP across a wide
range of sound intensities at their CF and frequencies other than CF.
Nevertheless, onEPSP recorded from layer 2 PNs changes its ampli-
 H. Ojima / Neuroscience and Biobehavioral Reviews 35 (2011) 2084–2093 2089

Fig. 5. Two representative response patterns of suppression found in the binaural interaction. (A) As shown in the upper panel, binaural stimulation (BIN) elicits a smaller
amplitude of an onEPSP, together with fewest spikes, when compared to an onEPSP amplitude elicited by the dominant (dom, IPSI) ear stimulation. The binaural suppression
of the onEPSP can be explained chiefly by linear summation of the response elicited at independent stimulation of each ear (i.e., IPSI dominant and CONTRA non-dominant
ear). For this neuron, as shown in the lower panel, non-dominant contralateral stimulation consistently elicits a strong IPSP at a wide range of stimulus intensities (20–80 dB
SPL). (B) Binaural stimulation elicits an onEPSP whose amplitude is almost equal to that elicited at non-dominant ear stimulation (non-dom, CONTRA) but much smaller
than that elicited at dominant ear stimulation (dom, IPSI). Simple summation of the responses evoked by independently stimulating each ear cannot account for the changed
amplitude of both EPSP and the following IPSP. Individual traces represent the average of 10 repeated trials. Arrowheads indicate resting membrane potential levels. Thick
horizontal lines show stimulus duration. Asterisks in A point to two hyperpolarizing deflection of the membrane potential. From Ojima and Murakami (2002).

tude in a non-monotonic manner. Thus, the onEPSP amplitude depending on the firing rate, although they do not display the best
decreases without accompanying an IPSP even as sound inten- intensity. Furthermore, without a systematic amplitude map across
sity increases (see Fig. 6, Ojima and Murakami, 2002). The absence the auditory cortex, how do non-monotonic neurons distinguish
of IPSP following the onEPSP can possibly be explained by differ- two intensity levels at which an equal magnitude of discharges
ences in the local networks in layer 2 and the recipient zone of TC is evoked, one lower and the other higher than the neuron’s best
afferents. Physiologically, PNs in the recipient zone are monosy- intensity? So far, there has been little evidence for a systematic
naptically driven by stimulation of TC afferent (Cruikshank et al., cortical amplitude map except in bats (Suga, 1977). Monotonic and
2002; Metherate and Cruikshank, 1999; Mitani and Shimokouchi, non-monotonic domains seem to be rather topographically orga-
1985; Rose and Metherate, 2001; Volkov and Galazjuk, 1991). It nized without forming an intensity map in the cat AI (Schreiner,
is known in AI that stimulation of the TC-recipient zone evokes 1992; Sutter and Schreiner, 1995).
EPSP in layer 2 PNs (Barbour and Callaway, 2008) as in motor
cortex (Kang et al., 1994). Thus, layer 2 PNs are likely to be a
7.2. Direct measurement of synaptic currents by in vivo
disynaptic target of TC afferents (Mitani et al., 1985), conforming
whole-cell patch clamp
to the findings in the visual system (Toyama et al., 1974; Ferster
and Lindström, 1983). Since a rich axon plexus from TC-recipient
Membrane potential measurements by conventional sharp
layer 3 PNs extends into layer 2 (Ojima et al., 1991, 1992), the
micro-electrodes in vivo have elucidated voltage changes caused
above findings suggest that tonally driven excitation carried by
by a net current as the consequence of linear summation of inward
TC afferents can reach layer 2 neurons polysynaptically via exci-
and outward currents (EPSC and IPSC) passing through respec-
tatory synapses of layer 3 PNs. A plausible interpretation is that
tive ligand-gated channels. However, the currents are not directly
these polysynaptic excitatory inputs cannot drive local interneu-
measured with this technique. Recent in vivo patch-clamp tech-
rons that are presynaptic to layer 2 PNs or bring their membrane
nique has allowed such measurements in the whole-cell voltage
potential only to a subthreshold level. The canonical circuitry may
clamp mode (Wehr and Zador, 2003; Zhang et al., 2003). It can
not be applicable here. Therefore, the non-monotonicity found in
separately measure excitatory and inhibitory currents by clamp-
layer 2 PNs would be inherited from cortical layer 3 PNs that are also
ing the membrane potential close to the equilibrium potentials for
non-monotonic in the their rate-level function. It can be implied
inhibitory and excitatory inputs, respectively, thus making it pos-
that connections would be formed between PNs located in differ-
sible to measure TC excitatory and cortical inhibitory contribution
ent layers of a column if their rate-level function is of the same
independently.
type.
The use of this technique has revealed that acoustically evoked
Are neurons having the best intensity defined from the non-
IPSC and EPSC are rather stereotyped in terms of their timing and
monotonic rate-level function the neuronal correlates for intensity
relative magnitude. Namely, an IPSC follows an onset EPSC with a
coding or loudness perception? On the basis of the findings
relatively constant delay time across a wide range of stimulus fre-
that increases in the neuronal proportion of non-monotonic type
quencies and intensities, implicating that the EPSC and IPSC interact
occur only in animals trained for loudness discrimination (Polley
minimally. Besides, although excitatory and inhibitory conduc-
et al., 2004, 2006), it is proposed that non-monotonic neurons are
tances vary widely according to the stimulus parameters, with the
involved in intensity encoding in such a way that they may change
maximum at the neuron’s CF, the ratio between them remains rel-
firing rates as a population in proportion to the increase in sound
atively constant. It indicates that they are balanced; namely, the
intensity. However, it seems premature to say that non-monotonic
contribution of inhibition to the creation of the response non-
neuronal population is solely responsible for loudness perception.
monotonicity is limited. In AI, therefore, the frequency tuning and
Monotonic neurons are presumably able to encode sound levels
intensity tuning might be generated without the interactions of
2090 H. Ojima / Neuroscience and Biobehavioral Reviews 35 (2011) 2084–2093
excitation and inhibition (Tan and Wehr, 2009; Wehr and Zador,
2003), implying that tuning properties of excitatory and inhibitory
inputs of AI neurons are inherited from the presynaptic TC neurons
in the vMGC.
However, in later studies, two forms of interaction between
EPSCs and IPSCs have been noted. EPSC and IPSC are unbalanced in
a subset of AI neurons. These interactions provide direct evidence
for the involvement of inhibition in cancelling out of the preceding
excitation according to a non-monotonic rate-level function, as pre-
viously suggested by the sharp microelectrode measurements. As
tone intensity increases, IPSC increases disproportionately and/or
its onset becomes much earlier compared to that elicited at
weaker sound intensities. Higher sound intensities thus lead to the
shortening of a delay time between the EPSC and IPSC, allowing
counteraction of the onset excitation with the inhibition following
it (Tan et al., 2007; Wu et al., 2008).
8. Synaptic activation in the binaural interaction
In the visual system, callosal axons projecting through the
corpus callosum (callosal projections) to the contralateral hemi-
sphere terminate in a restricted zone bordering between areas
17 and 18 (Fisken et al., 1975; Harvey, 1980; Shatz, 1977). In
contrast, terminal axons of auditory callosal projections are exten-
sively distributed across AI (Code and Winer, 1986; Imig and
Brugge, 1978; Rüttgers et al., 1990; Wallace and Harper, 1997).
However, they are not homogenously distributed but constitute
multiple bands across the AI cortex in cats and ferrets (Imig and
Brugge, 1978; Imig and Reale, 1981; but see Brandner and Redies,
1990). It is thought that these callosal bands are interleaved with
zones containing predominantly terminals of association neurons.
The callosal and association zones are assumed to be function-
ally different and referred to as, respectively, EE and EI binaural
interaction bands. In EE bands, neurons show facilitation at binau-
ral stimulation (i.e., binaural response magnitude is greater than
monaural response magnitude), while in EI bands, neurons show
suppression at binaural stimulation (i.e., response magnitude at
dominant ear stimulation is greater than that at binaural stim-
ulation). Some neurons display responses only to stimulation of
one ear (EO binaural interaction) and seem to be dispersed across
the AI cortex without constituting distinct bands (Imig and Brugge,
1978).
It should be noted that the binaural interaction does not sim-
ply represent the interaction between ipsilateral and contralateral
acoustic inputs per se. In the auditory ascending pathway, because
of the commissural projections at two subcortical levels (the
cochlear nucleus and the inferior colliculus), acoustic stimulation
to one ear eventually induces bilateral activation at any level.
Since each hemisphere receives callosal projections from the oppo-
site hemisphere (anatomically; Code and Winer, 1986; Imig and
Brugge, 1978; Rüttgers et al., 1990; Wallace and Harper, 1997)
(physiologically; Goycoolea et al., 2005; Kitzes and Doherty, 1994;
Mitani and Shimokouchi, 1985), it is highly possible that monaural
stimulation alone can drive cortical neurons in each hemisphere.
This is by way of TC projections ipsilaterally and callosal inputs
contralaterally. Therefore, elucidating the binaural interactions is
tantamount to characterizing the composite PSPs elicited by con-
currently activated TC and callosal inputs to PNs and to examine
how different the composite responses are among different aural
stimulation styles. Also, ‘binaural stimulation’ generally means the
bilateral presentation of a tone at the same frequency, intensity, and
phase. Thus, it may correspond to stimulation at the zero azimuthal
point in the free field.
Intracellular recording of PSPs typically showed a stereotyped
sequence of an onEPSP followed by an IPSP at any style of aural stim-
ulation. However, the amplitude and latency of these PSPs varied
considerably depending on which ear was stimulated (Ojima and
Murakami, 2002). Some responses at binaural stimulation, nev-
ertheless, can be explained by the linear summation of the PSPs
elicited by independent stimulation of each ear. As exemplified
by an EI neuron in Fig. 5A, monaural, dominant ear stimulation
evoked a typical sequence of the PSPs (Fig. 5A, upper). Monaural,
non-dominant ear stimulation evoked an IPSP alone without a pre-
ceding EPSP across a wide frequency range (Fig. 5A, lower). This
IPSP coincided with the EPSP evoked by the dominant, opposite ear
stimulation. Therefore, if spatial and temporal summation holds
true, simultaneous stimulation of two ears (binaural stimulation)
predicts a decreased level of the evoked EPSP, leading to decreased
discharges representing the EI type of binaural interaction.
In some EI neurons, however, linear summation cannot ade-
quately explain the reduction in onEPSP amplitude. Fig. 5B shows
that the onEPSP amplitude at binaural stimulation is almost equal
to that at monaural, non-dominant ear stimulation. The EPSP at
dominant ear stimulation, by definition, is larger in amplitude than
that at the non-dominant ear stimulation, and therefore larger than
that at the binaural stimulation. Thus, if linear summation under-
pins the binaural interaction, it would be predicted that the sum
of the non-dominant and dominant ear responses be larger than
either of the component monaural responses. In reality, however,
this summation representing the binaural response does not yield
such increased responses.
Alternative interpretation might adopt the mechanisms of
suppression underlying the non-monotonic rate-level function.
Because the auditory ascending pathway is basically bilateral, bin-
aural stimulation is likely to recruit more projections, thereby
driving cortical neurons more intensively, than monaural stimu-
lation. Binaural stimulation therefore is comparable to stimulation
at higher sound intensities (Semple and Kitzes, 1993a,b; Zhang et
al., 2004). Namely, the reduced amplitude of onEPSP at binaural
stimulation would be a consequence of more intensive stimulation
of non-monotonic neurons than at monaural stimulation. However,
this does not seem to be the case. According to one of the mech-
anisms underlying the non-monotonic rate-level function, an IPSP
becomes elicited so earlier as to counteract the preceding EPSP at
higher sound intensities (Ojima and Murakami, 2002; Wu et al.,
2006). However, as shown in Fig. 5B, there is no such shorten-
ing of the onset latency of the IPSP at the binaural stimulation
compared to that at the non-dominant ear stimulation. Similarly,
according to another mechanism, an IPSP becomes augmented to
a level sufficient to unbalance the preceding EPSP. However, no
such growth of the IPSP is associated with the onEPSP at the binau-
ral stimulation. Thus, the underlying mechanisms are different and
likely include some nonlinear interactions. These remain to be yet
examined.
Recordings from most of the so-called EO PNs showed no
substantial differences in the magnitude and latency of onEPSP
between the dominant ear stimulation and the binaural stimula-
tion. Shaping of responses by inhibition is likely to be minimal,
although some EO neurons had an IPSP following an onEPSP. Since
the responses evoked by binaural stimulation do not differ from
those evoked by dominant ear stimulation, at least two patterns of
responses to the non-dominant ear stimulation could be assumed.
In one pattern, non-dominant ear stimulation would generate null
onset response; neither EPSP nor IPSP is evoked at the stimulus
onset. In the other pattern, non-dominant ear responses would
be temporally lagged behind dominant ear responses to such an
extent that these two responses could not coincide; the possibility
of the temporal interaction between the two responses is minimal
in this pattern. In reality, with the exception of a single neuron,
no membrane potential change was evoked by non-dominant ear
stimulation (14/15, unpublished observation). Thus, like some EI
 H. Ojima / Neuroscience and Biobehavioral Reviews 35 (2011) 2084–2093
neurons, EO binaural interaction can simply be explained by the
linear summation of PSP evoked separately by stimulation of each
ear alone.
Although neurons showing the same binaural interaction prop-
erties tend to be arranged in a columnar fashion in the AI cortex
(Imig and Adrián, 1977), the roles that neurons with different bin-
aural interaction properties play in the localization of a sound
source are little understood. An important question is how inhibi-
tion grows or how it interacts with the preceding EPSPs if sound
source location shifts in a systematic manner, or more specifi-
cally, in the systematic changing of the interaural time or level
difference. This may not be available at present, but recent in vivo
measurements of PSPs evoked by a noise emitted from various spa-
tial locations revealed the occurrence of subEPSP with substantial
amplitudes even at locations much deviated from the neuron’s pre-
ferred location where the EPSP amplitude (therefore, the firing rate
of APs) was maximal (Chadderton et al., 2009). It also suggested the
possible involvement of the steepness of the onEPSP rising phase
in the detection of the sound source by cortical neurons. Further
studies at the synaptic level will be awaited.
9. Conclusions
Synaptic mechanisms underlying the spike rate changes evoked
by changing acoustic attributes were originally explored by
measuring membrane potentials in vivo. The depolarizing and
hyperpolarizing shifts in membrane potential have revealed the
importance of inhibitory synaptic input in shaping the spatiotem-
poral response field of single PNs. Direct in vivo measurements
of synaptic currents have refined these mechanisms and clarified
the mechanisms for precise interactions of the strength and tim-
ing of excitatory/inhibitory synaptic conductance in the receptive
field shaping. This approach has been extended even to suggest
non-linear interactions of excitation and inhibition (Machens et al.,
2004), importance of the spike generation mechanism (Ye et al.,
2010), and laminar specificity of processing of acoustic signals
(Zhou et al., 2010) in the auditory system. Auditory cortex seems to
be influenced by non-auditory signals or even by the brain internal
state (Ojima et al., 2010). One of the ultimate goals in the auditory
sensory physiology is to describe the interactions of sensory infor-
mation and memory-based internal information at the synaptic
level.
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